Pneumococcal pneumonia is a leading cause of infection-related deaths in the United States. During pneumococcal pneumonia, an intense inflammatory reaction occurs that involves local cytokine production, neutrophil emigration, and the extravasation of plasma constituents. The pathophysiological outcome of infectious pneumonia is largely based on bacteria-induced cytokine signaling that regulates the expression of proinflammatory genes through the NF-?B pathway. Previous studies from our lab have shown that in response to bacterial stimuli in the lungs, NF-?B RelA is essential for the transcription of chemokines and adhesion molecules that mediate neutrophil recruitment. Furthermore, interrupting RelA was shown to seriously compromise bacterial clearance from the lungs. In terms of understanding the role of specific cell types in the lung during pneumonia, our lab has also shown that alveolar macrophages, which are the first leukocytes to encounter pathogens in the lung, secrete cytokines that are dependent upon NF-?B and critical to lung defense. Pneumococcus colonizes the nasopharynx of most children during the first few years of life. However, pneumococcal nasopharyngeal colonization can progress into the lower respiratory tract, where life- threatening disease can be initiated. Currently, there are over 90 different serotypes of pneumococcus, and much of what is known about disease progression is often serotype focused. Although a prominent virulence factor, serotype alone does explain why pneumococcal disease in some individuals progresses to invasive disease but not in others. This observation is further complicated by the fact that even within a given serotype different isolates have varying abilities to cause disease; which would suggest that these differences were due to virulence factors independent of the capsule. Elucidation of other virulence determinants would greatly enhance our understanding of the range of disease pathogenesis seen in patients. We propose to uncover the molecular mechanisms (such as macrophage NF-?B activation and cytokine expression) that direct innate immunity in the lungs during pneumococcal infection and examine whether pneumococcal subversion of this response is a critical virulence determinant. We hypothesize that different pneumococcal isolates vary in their ability to activate macrophage NF-?B and those that subvert macrophage activation are more capable of causing severe pneumonia. The biological insights gained from these studies will help us better understand whether host responses to pneumococcus are critical determinants of infection in order to identify susceptible individuals and particularly virulent pneumococci. PUBLIC HEALTH RELEVANCE: Pneumococcal pneumonia is a major cause of disease worldwide and causes significant annual morbidity and mortality in the U.S. Our goal is to better understand how a specific signaling pathway in select immune cells (NF-KB in macrophages) dictates the outcome of lung infection with this bacteria. This knowledge will guide future studies aiming to identify especially susceptible individuals and especially virulent bacteria.